Method of enhancing hair growth

ABSTRACT

Methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I 
     
       
         
         
             
             
         
       
     
     wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, A, B, Z, X, R 1  and R 2  are as defined in the specification. Such compositions are used in treating the skin or scalp of a human or non-human animal. Bimatoprost is preferred for this treatment.

RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 11/943,714, filed Nov. 21, 2007, which is a continuation ofU.S. patent application Ser. No. 11/805,122, filed May 22, 2007, whichis a continuation of U.S. patent application Ser. No. 10/345,788 whichwas filed on Jan. 15, 2003, which claims the benefit of U.S. ProvisionalApplication No. 60/354,425, filed on Feb. 4, 2002, hereby incorporatedby reference herein.

FIELD OF THE INVENTION

This invention relates to a method for stimulating the growth ofmammalian hair comprising the application to mammalian skin of acyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivative or apharmacologically acceptable acid addition salt thereof, alone, or inassociation with a topical pharmaceutical carrier.

BACKGROUND OF THE INVENTION

Dermatologists recognize many different types of hair loss, the mostcommon by far being “alopecia” wherein human males begin losing scalphair at the temples and on the crown of the head as they get older.While this type of hair loss is largely confined to males, hence itscommon name “male pattern baldness,” it is not unknown in women. Noknown cure has yet been found despite continuing attempts to discoverone.

A good deal is known about various types of human hair and its growthpatterns on various parts of the body.

For purposes of the present invention, it is necessary to considervarious types of hair, including, terminal hairs and vellus hairs andmodified terminal hairs, such as seen in eye lashes and eye brows.Terminal hairs are coarse, pigmented, long hairs in which the bulb ofthe hair follicle is seated deep in the dermis. Vellus hairs, on theother hand, are fine, thin, non-pigmented short hairs in which the hairbulb is located superficially in the dermis. As alopecia progresses, atransition takes place in the area of approaching baldness wherein thehairs themselves are changing from the terminal to the vellus type.

Another factor that contributes to the end result is a change in thecycle of hair growth. All hair, both human and animal, passes through alife cycle that includes three phases, namely, the anagen phase, thecatagen phase and the telogen phase. The anagen phase is the period ofactive hair growth and, insofar as scalp hair is concerned, thisgenerally lasts from 3-5 years. The catagen phase is a shorttransitional phase between the anagen and telogen phases which, in thecase of scalp hair, lasts only 1-2 weeks. The final phase is the telogenphase which, for all practical purposes, can be denominated a “restingphase” where all growth ceases and the hair eventually is shedpreparatory to the follicle commencing to grow a new one. Scalp hair inthe telogen phase is also relatively short-lived, some 3-4 monthselapsing before the hair is shed and a new one begins to grow.

Under normal hair growth conditions on the scalp, approximately 88% ofthe hairs are in the anagen phase, only 1% in catagen and the remainderin telogen. With the onset of male pattern baldness, a successivelygreater proportion of the hairs are in the telogen phase withcorrespondingly fewer in the active growth anagen phase.

Alopecia is associated with the severe diminution of hair follicles. Abald human subject will average only about 306 follicles per squarecentimeter, whereas, a non-bald human in the same age group will have anaverage of 460 follicles per square centimeter. This amounts to aone-third reduction in hair follicles which, when added to the increasedproportion of vellus hair follicles and the increased number of hairfollicles in the telogen phase, is both significant and noticeable.Approximately 50% of the hairs must be shed to produce visible thinningof scalp hair. It is thus a combination of these factors: transition ofhairs from terminal to vellus, increased number of telogen hairs—some ofwhich have been shed, and loss of hair follicles that produces“baldness”.

While a good deal is known about the results of male pattern baldness,very little is known about its cause. The cause is generally believed tobe genetic and hormonal in origin although, the known prior art attemptsto control it through hormone adjustment have been singularlyunsuccessful.

One known treatment for male pattern alopecia is hair transplantation.Plugs of skin containing hair are transplanted from areas of the scalpwhere hair is growing to bald areas with reasonable success; however,the procedure is a costly one in addition to being time-consuming andquite painful. Furthermore, the solution is inadequate from thestandpoint that it becomes a practical, if not an economic,impossibility to replace but a tiny fraction of the hair present in anormal healthy head of hair.

Other non-drug related approaches to the problem include such things asultra-violet radiation, massage, psychiatric treatment and exercisetherapy. None of these, however, has been generally accepted as beingeffective. Even such things as revascularization surgery and acupuncturehave shown little, if any, promise.

By far, the most common approach to the problem of discovering a remedyfor hair loss and male pattern alopecia has been one of drug therapy.Many types of drugs ranging from vitamins to hormones have been triedand only recently has there been any indication whatsoever of evenmoderate success. For instance, it was felt for a long time that sincean androgenic hormone was necessary for the development of male patternbaldness, that either systemic or topical application of anantiandrogenic hormone would provide the necessary inhibiting action tokeep the baldness from occurring. The theory was promising but theresults were uniformly disappointing.

The androgenic hormone testosterone was known, for example, to stimulatehair growth when applied topically to the deltoid area as well as wheninjected into the beard and pubic regions. Even oral administration wasfound to result in an increased hair growth in the beard and pubic areasas well as upon the trunk and extremities. While topical application tothe arm causes increased hair growth, it is ineffective on the scalp andsome thinning may even result. Heavy doses of testosterone have evenbeen known to cause male pattern alopecia.

Certain therapeutic agents have been known to induce hair growth inextensive areas of the trunk, limbs and even occasionally on the face.Such hair is of intermediate status in that it is coarser than vellusbut not as coarse as terminal hair. The hair is generally quite shortwith a length of 3 cm. being about maximum. Once the patient ceasestaking the drug, the hair reverts to whatever is normal for theparticular site after six months to a year has elapsed. An example ofsuch a drug is diphenylhydantoin which is an anticonvulsant drug widelyused to control epileptic seizures. Hypertrichosis is frequentlyobserved in epileptic children some two or three months after startingthe drug and first becomes noticeable on the extensor aspects of thelimbs and later on the trunk and face. (The same pattern ofhypertrichosis is sometimes caused by injury to the head.) As for thehair, it is often shed when the drug is discontinued but may, in somecircumstances, remain.

Streptomycin is another drug that has been found to producehypertrichosis, in much the same way as diphenylhydantoin, whenadministered to children suffering from tuberculous meningitis. Aboutthe same effects were observed and the onset and reversal of thehypertrichosis in relation to the period of treatment with theantibiotic leave little question but that it was the causative agent.

Two treatments have been demonstrated as showing some promise inreversing male pattern alopecia. These treatments include the use of amicroemulsion cream containing both estradiol and oxandrolone as itsactive ingredients and the use of organic silicon.

In addition to the foregoing, it has been reported in U.S. Pat. Nos.4,139,619 and 4,968,812 that the compound minoxidil is useful for thetreatment of male pattern baldness. That compound, among others, hasproven to have considerable therapeutic value in the treatment of severehypertension. It is a so-called “vasodilator” which, as the nameimplies, functions to dilate the peripheral vascular system.Dermatologists and others have recognized that prolonged vasodilation ofcertain areas of the human body other than the scalp sometimes result inincreased hair growth even in the absence of any vasodilatingtherapeutic agent. For instance, increased hair growth around surgicalscars is not uncommon. Similarly, arteriovenous fistula have been knownto result in increased vascularity accompanied by enhanced hair growth.Externally-induced vasodilation of the skin, such as, for example, byrepeated biting of the limbs by the mentally retarded and localizedstimulation of the shoulders by water carries has been known to bring onhypertrichosis in the affected areas. Be that as it may, similartechniques such as continued periodic massage of the scalp have beenfound to be totally ineffective as a means for restoring lost hairgrowth to the scalp. Scar tissue on the scalp inhibits rather thanpromotes hair growth.

U.S. Pat. No. 6,262,105 to Johnstone suggests that prostaglandins andderivatives thereof are useful in a method of enhancing hair growth.

Bimatoprost, which is sold by Allergan, Inc. of Irvine, Calif., U.S.A.as Lumigan® ophthalmic solution, for treating glaucoma now has beenfound as being effective to increase the growth of eyelashes whenapplied in the FDA approved manner.

It is, therefore, a principal object of the present invention to providea novel and effective treatment for the stimulation of hair growth andthe treatment of male pattern baldness.

Another object of the invention is to provide a method of stimulatinghair growth in humans and non-human animals that is compatible withvarious types of therapeutic agents or carriers and, therefore, wouldappear to be combinable with those which, by themselves, demonstratesome therapeutic activity such as, for example, microemulsion creams ortopical compositions containing estradiol and oxandrolone, minoxidil oragents that block the conversion of testosterone to dihydrotesterone(Procipia).

Still another objective is the provision of a treatment for thestimulation of hair growth which, while effective for its intendedpurpose, is apparently non-toxic and relatively free of unwanted sideeffects.

An additional object of the invention herein disclosed and claimed is toprovide a method for treating hair loss in men or women which can beapplied by the patient under medical supervision no more stringent thanthat demanded for other topically-administered therapeutic agents.

Other objects of the invention are to provide a treatment for malepattern alopecia which is safe, simple, painless, cosmetic in the senseof being invisible, easy to apply and quite inexpensive when comparedwith hair transplants and the like.

SUMMARY OF THE INVENTION

This invention provides pharmaceutical compositions for topicalapplication to enhance hair growth comprising an effective amount of acyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compoundrepresented by the formula I

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration, A is an alkylene or alkenyleneradical having from two to six carbon atoms, which radical may beinterrupted by one or more oxa radicals and substituted with one or morehydroxy, oxo, alkyloxy or akylcarboxy groups wherein said alkyl radicalcomprises from one to six carbon atoms; B is a cycloalkyl radical havingfrom three to seven carbon atoms, or an aryl radical, selected from thegroup consisting of hydrocarbyl aryl and heteroaryl radicals having fromfour to ten carbon atoms wherein the heteroatom is selected from thegroup consisting of nitrogen, oxygen and sulfur atoms; X is —N(R⁴)²wherein R⁴ is selected from the group consisting of hydrogen, a loweralkyl radical having from one to six carbon atoms,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)mR₇ wherein m is 0 or an integer of from1 to 10, and R₇ is cycloalkyl radical, having from three to seven carbonatoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above infree form or a pharmaceutically acceptable salt thereof, in associationwith a pharmaceutical carrier adapted for topical application tomammalian skin.

Preferably, the compound is a cyclopentane heptanoic acid, 2-(phenylalkyl or phenyloxyalkyl) represented by the formula II

wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is aradical selected from the group consisting of alkyl, halo, e.g. fluoro,chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, halosubstituted alkyl wherein said alkyl radical comprises from one to sixcarbon atoms, etc. and n is 0 or an integer of from 1 to 3 and R₃ is ═O,—OH or —O(CO)R₆ wherein R₆ is as defined above or a pharmaceuticallyacceptable salt thereof.

More preferably the compound is a compound of formula III.

wherein hatched lines indicate cc configuration, solid triangles areused to indicate β configuration.

More preferably y is 1 and x is 0 and R₁, R₂ and R₃ are hydroxy.

Most preferably the compound is cyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1₆₀ ,2_(β),3_(α), 5₆₀ ] also known as bimatoprost.

Another aspect of the invention provides methods for stimulating therate of hair growth and for stimulating the conversion of vellus hair orintermediate hair to growth as terminal hair in a human or non-humananimal by administering to the skin of the animal an effective amount ofa compound wherein the compound has the formula:

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration, A is an alkylene or alkenyleneradical having from two to six carbon atoms, which radical may beinterrupted by one or more oxa radicals and substituted with one or morehydroxy, oxo, alkyloxy or akylcarboxy groups wherein said alkyl radicalcomprises from one to six carbon atoms; B is a cycloalkyl radical havingfrom three to seven carbon atoms, or an aryl radical, selected from thegroup consisting of hydrocarbyl aryl and heteroaryl radicals having fromfour to ten carbon atoms wherein the heteroatom is selected from thegroup consisting of nitrogen, oxygen and sulfur atoms; X is —N(R⁴)₂wherein R⁴ is selected from the group consisting of hydrogen, a loweralkyl radical having from one to six carbon atoms,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)mR₇ wherein m is 0 or an integer of from1 to 10, and R₇ is cycloalkyl radical, having from three to seven carbonatoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above infree form or a pharmaceutically acceptable salt thereof.

These and other aspects of the invention will become apparent from thedescription of the invention which follows below.

BRIEF DESCRIPTION OF THE DRAWING FIGURE

The FIGURE shows the effect on the eyelashes of one patient treated forglaucoma with Lumigan® bimatoprost for six months.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Alopecia (baldness) a deficiency of either normal or abnormal hair, isprimarily a cosmetic problem in humans. It is a deficiency of terminalhair, the broad diameter, colored hair that is readily seen. However, inthe so-called bald person although there is a noticeable absence ofterminal hair, the skin does contain vellus hair which is a finecolorless hair which may require microscopic examination to determineits presence. This vellus hair is a precursor to terminal hair. Inaccordance with the invention as described herein, compounds representedby

wherein R₁, R₂, A, B, Z and X are defined above, can be used tostimulate, such as stimulating the conversion of vellus hair to growthas terminal hair as well as increasing the rate of growth of terminalhair.

The present invention was discovered as follows:

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice it wasdiscovered that a patient who been treated with bimatoprost has lashesthat were longer, thicker and fuller in the treated eye than in thenon-treated eye. On examination the difference was found to be verystriking. The lashes were longer and had a more full dense appearance inthe treated eye. The lash appearance on the lids of the treated eyewould have appeared quite attractive if it represented a bilateralphenomenon. Because of its asymmetric nature, the long lashes on oneside could be construed as disturbing from a cosmetic standpoint.Because of the very unusual appearance a systematic examination of otherpatients who were taking bimatoprost in only one eye was made. It soonbecame apparent that this altered appearance was not an isolatedfinding. Comparison of the lids of patients who were taking bimatoprostin only one eye revealed subtle changes in the lashes and adjacent hairsof the bimatoprost-treated side in several patients. Definitedifferences could be identified to varying degrees in the lashes andadjacent hairs of all patients who were taking the drug on a unilateralbasis for longer than 6 months.

These findings were totally unexpected and surprising. Minoxidil isthought to stimulate hair growth by its ability to cause vasodilationsuggesting that agents with such a capability may be uniquely effectivein stimulating hair growth. The finding that bimatoprost, which, asexplained below, is not a prostaglandin derivative, such as latanoproststimulates hair growth is especially surprising and unexpected.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of a glaucoma follow up examination,attention is generally immediately focused on the eye itself. Because ofthe high power magnification needed only one eye is seen at a time andthe eye is seen at a high enough power that the lashes are not in focus.At these higher powers, any lash asymmetry between the two eyes is notlikely to be noticed except by careful systematic comparison of thelashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treated area following administration ofbimatroprost were multiple. They included increased length of lashes,increased numbers of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased lash-like terminal hairs at the medial and lateral canthalarea, increased pigmentation of the lashes, increased numbers, increasedlength, as well as increased luster, and thickness of fine hair on theskin of the adjacent lid, and finally increased perpendicular angulationof lashes and lash-like terminal hairs. The conclusion that hair growthis stimulated by bimatoprost is thus supported not by evidence of adifference in a single parameter but is based on multiple parameters ofhair appearance in treated vs. control areas in many subjects. Thisfinding is entirely unexpected and represents a previously unrecognizedeffect of bimatoprost on stimulation of hair follicles. The modifiedhairs of the lashes normally turn over slowly and are in their restingphase longer than hair on, for example, the scalp. The ability to causedifferences in appearance of lashes, the ability to stimulate conversionof vellus or intermediate hair to terminal hairs in transitional areasand the ability to stimulate growth of vellus hair on the skin indicatesthat bimatoprost is a diversely effective and efficacious agent for thestimulation of hair growth. Thus, the present invention provides atreatment by bimatoprost of hair of the scalp, eyebrows, beard and otherareas that contain hair that results in increased hair growth in thecorresponding areas.

Patients that are treated in or around the eye with compounds of theinvention, such as bimatoprost, regularly develop hypertrichosisincluding altered differentiation, numbers, length, thickness, curvatureand pigmentation in the region of treatment.

Some examples of representative compounds useful in the practice of thepresent invention include the compounds shown in Table 1:

TABLE 1 cyclopentane heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5₆α] cyclopentaneN,N-dimethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethyl-phenoxy-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)]cyclopentane N-isopropyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)] cyclopentaneN-ethyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1- trans-pentenyl)-3,5dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)] cyclopentane N-methylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)] cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-butenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α,) 5_(α)]

One presently preferred compound for use in the practice of the presentinvention is cyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(β),3_(α), 5_(α)], also known as bimatoprost and sold under thename of Lumigant by Allergan, Inc., California, USA. This compound hasthe following structure:

The synthesis of the above compounds described above has been disclosedin U.S. Pat. No. 5,607,978. This patent also shows, particularly inExamples 1, 2, 5 and 7 that these compounds are not prostaglandins, inthat they do not behave as prostaglandins in art-recognized assays forprostaglandin activity. The invention thus relates to the use of theabove compounds, or prodrugs of the active compounds, for treatment forthe stimulation of hair growth. As used herein, hair growth includeshair associated with the scalp, eyebrows, eyelids, beard, and otherareas of the skin of animals.

In accordance with one aspect of the invention, the compound is mixedwith a dermatologically compatible vehicle or carrier. The vehicle whichmay be employed for preparing compositions of this invention maycomprise, for example, aqueous solutions such as e.g., physiologicalsalines, oil solutions or ointments. The vehicle furthermore may containdermatologically compatible preservatives such as e.g., benzalkoniumchloride, surfactants like e.g., polysorbate 80, liposomes or polymers,for example, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidoneand hyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

The invention is also related to dermatological compositions for topicaltreatment for the stimulation of hair growth which comprise an effectivehair growth stimulating amount of one or more compounds as defined aboveand a dermatologically compatible carrier. Effective amounts of theactive compounds may be determined by one of ordinary skill in the artbut will vary depending on the compound employed, frequency ofapplication and desired result, and the compound will generally rangefrom about 0.0000001 to about 50%, by weight, of the dermatologicalcomposition, preferably. from about 0.001 to about 50%, by weight, oftotal dermatological composition, more preferably from about 0.1 toabout 30%, by weight of the composition.

The present invention finds application in all mammalian species,including both humans and animals. In humans, the compounds of thesubject invention can be applied for example, to the scalp, face, beard,head, pubic area, upper lip, eyebrows, and eyelids. In animals raisedfor their pelts, e.g., mink, the compounds can be applied over theentire surface of the body to improve the overall pelt for commercialreasons. The process can also be used for cosmetic reasons in animals,e.g., applied to the skin of dogs and cats having bald patches due tomange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated by this invention includepharmaceutical compositions suited for topical and local action.

The term “topical” as employed herein relates to the use of a compound,as described herein, incorporated in a suitable pharmaceutical carrier,and applied at the site of thinning hair or baldness for exertion oflocal action. Accordingly, such topical compositions include thosepharmaceutical forms in which the compound is applied externally bydirect contact with the skin surface to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds are applied repeatedly for a sustained periodof time topically on the part of the body to be treated, for example,the eyelids, eyebrows, skin or scalp. The preferred dosage regimen willgenerally involve regular, such as daily, administration for a period oftreatment of at least one month, more preferably at least three months,and most preferably at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments or oils exhibitingphysiologically acceptable osmolarity by addition of pharmacologicallyacceptable buffers and salts. Such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid etc.as additives. Furthermore, particularly aqueous solutions may containviscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matrices may also be employed as well as solubleand insoluble ocular inserts, for instance, based on substances formingin-situ gels. Depending on the actual formulation and compound to beused, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and the scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matrices for slow releasedelivery may also be used. Typically, the dose to be applied on thescalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

The invention is further illustrated by the following non-limitingexamples:

EXAMPLE 1 In Vivo Treatment

A study is initiated to systematically evaluate the appearance of lashesand hair around the eyes of patients who are administering bimatoprostin only one eye. The study involves 10 subjects, 5 male, 5 female,average age 70 years, (ranging from 50-94 years). All patients haveglaucoma. Each subject is treated daily by the topical application ofone drop of bimatoprost at a dosage of 1.5 .mu.g/ml/eye/day (0.03%, byweight, ophthalmic solution, sold under the name Lumigan® by Allergan,Irvine, Calif., U.S.A.) to the region of one eye by instilling the droponto the surface of the eye. The region of the fellow control eye is nottreated with bimatoprost and served as a control.

In the course of treatment with eye drops, there is typicallyspontaneous tearing, and excess fluid from the drops and associatedtears gathers at the lid margins. In the course of wiping the drugcontaining fluid from the lid margins and adjacent lid, a thin film ofthe fluid is routinely spread to contact the adjacent skin of the lidarea. This widespread exposure of the skin around the lid to the effectof drops is regularly demonstrated in patients who develop a contactdermatitis. Typically the entire area of the upper and lower lid areinvolved with induration, erythema and edema demonstrating the regularextensive exposure of the ocular adnexa to the influence of topicallyapplied drugs.

The study is limited to subjects who have administered bimatoprost toone eye for more than 3 months. The mean duration of exposure tobimatoprost prior to assessing the parameter of lash growth between thecontrol and study eye is 129 days (range 90-254 days). Observations aremade under high magnification at the slit lamp biomicroscope.Documentation of differences between the control and treatment areas isaccomplished using a camera specially adapted for use with the slit lampbiomicroscope.

The results of the observations are as follows: Length of lashes:Increased length of eyelashes is regularly observed on the side treatedwith bimatoprost. The difference in length varies from approximately 10%to as much as 30%.

Number of lashes: Increased numbers of lashes are observed in thetreated eye of each patient. In areas where there are a large number oflashes in the control eye, the increased number of lashes in thebimatoprost-treated eye gave the lashes on the treated side a morethickly matted overall appearance.

Auxiliary lash-like hair growth: Several patients have an apparentincrease in lash-like hair in transitional areas adjacent to areas ofnormal lash distribution. These prominent robust appear lash-like hairsappeared to be of comparable length to the actual lashes. These long,thick lash-like hairs were present in the central portion of the lids ofseveral patients in a linear arrangement just above the lash line. Hairsare present at similar locations in the control eyes but are by contrastthinner or more fine in appearance, have less luster and pigment and aremore flat against the skin of the lid typical of vellus or intermediatehairs. In several patients, lash-like terminal hairs grow luxuriantly inthe medial canthal area in the treated eye. In the corresponding controleye, vellus hairs are seen at the same location. Lash-like hairs arealso present in the lateral canthal area of the treated eye but not thecontrol eye in several subjects. Large lashes are not normally presentat the lateral canthus and the area is generally free of all but a fewoccasional very fine lashes or vellus hairs.

Increased growth of vellus hair on lids: Fine microscopic vellus hair ispresent on the skin of the lids and is easily seen with the slit lampbiomicroscope. This vellus hair is typically denser adjacent to andbelow the lateral portion of the lower lids. While remainingmicroscopic, vellus hairs are increased in number, appear more robustand are much longer and thicker in treated than in control eyes in theareas below and lateral to the lower lid.

Perpendicular angulation of hairs: In areas where there are lash-likehairs above the lash line and in the medial and lateral canthal areas,the hairs are much longer, thicker and heavier. They also leave thesurface of the skin at a more acute angle, as though they are stiffer orheld in a more erect position by more robust follicles. This greaterincline, pitch, rise or perpendicular angulation from the skin surfacegives the appearance of greater density of the hairs.

The foregoing observations clearly establish that bimatoprost can beused to increase the growth of hair in man. This conclusion is based onthe regular and consistent finding of manifestations of increased hairgrowth in treated vs. control areas in human subjects. The conclusionthat the drug bimatoprost is capable of inducing increased robust growthof hair is based not on a single parameter, i.e., length, but is basedon multiple lines of evidence as described in the results. Detailedexamination and description of multiple parameters of differences inhair is greatly facilitated by the ability to examine the hairs at highmagnification under stable conditions of fixed focal length and subjectposition utilizing the capabilities of the slitlamp biomicroscope.

The Figure shows the actual results on the eyelashes of a patienttreated for glaucoma with Lumigan® bimatoprost for 6 months.

EXAMPLE 2 Topical Cream

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin about 500 gm of water and propylene glycol, polysorbate 80, andbimatoprost are added in turn, maintaining a temperature of 75-80° C.The methylparaben mixture is added slowly to the Tegacid and spermacetimelt, with constant stirring. The addition is continued for at least 30minutes with additional stirring until the temperature has dropped to40-45° C. Finally, sufficient water is added to bring the final weightto 1000 gm and the

preparation stirred to maintain homogeneity until cooled and congealed.

EXAMPLE 3 Topical Cream

A topical cream is prepared as follows: Tegacid and spermaceti aremelted together at a temperature of 70-80° C. Methylparaben is dissolvedin water and propylene glycol, polysorbate 80, and bimatoprost are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to the Tegacid and spermaceti melt, withconstant stirring. The addition is continued for at least 30 minuteswith additional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

The composition is applied to bald human scalp once daily to stimulatethe growth of hair.

EXAMPLE 4 Topical Ointment

An ointment containing 2% by weight bimatoprost is prepared as follows:

White petrolatum and wool fat are melted, strained and liquid petrolatumis added thereto. The bimatoprost, zinc oxide, and calamine are added tothe remaining liquid petrolatum and the mixture milled until the powdersare finely divided and uniformly dispersed. The mixture is stirred intothe white petrolatum, melted and cooled with stirring until the ointmentcongeals.

The foregoing ointment can be applied topically to mammalian skin forincreased rate of hair growth, and can be prepared by omitting the zincoxide and calamine.

EXAMPLE 5 Ointment

A dermatological ophthalmic ointment containing 10% by weightbimatoprost is prepared by adding the active compound to light liquidpetrolatum. White petrolatum is melted together with wool fat, strained,and the temperature adjusted to 45-50° C. The liquid petrolatum slurryis added and the ointment stirred until congealed. Suitably the ointmentis packaged in 30 gm tubes.

The foregoing ointment can be applied to the eyelid to enhance thegrowth of eyelashes. Similarly the composition can be applied to thebrow for eyebrow growth.

EXAMPLE 6 Solution

An aqueous solution containing 5%, by weight, bimatoprost is prepared asfollows. Bimatoprost is dissolved in water and the resulting solution issterilized by filtration. The solution is aseptically filled intosterile containers.

The composition so prepared can be used in the topical treatment ofbaldness by application to the scalp daily.

EXAMPLE 7 Lotion

A sample of bimatoprost is dissolved in the vehicle of N-methylpyrrolidone and propylene glycol. The composition can be used forapplication to dogs or cats

having hair loss due to mange or alopecia of other causes.

EXAMPLE 8 Aerosol

An aerosol containing approximately 0.1% by weight bimatoprost isprepared by dissolving the bimatoprost in absolute alcohol. Theresulting solution filtered to remove particles and lint. This solutionis chilled to about minus 30° C. To the solution is added a chilledmixture of dichlorodifluoromethane and dichlorotetrafluoroethane.

Thirteen ml plastic-coated amber bottles are cold filled with 11.5 gmeach of the resulting solution and capped.

The composition can be sprayed on the scalp daily to stimulate thegrowth of hair.

EXAMPLE 9 Dusting Powder

A powder of the compound bimatoprost is prepared by mixing in dry formwith talcum powder at a weight/weight ratio of 1:10. The powderedmixture is dusted on the fur of minks or other commercially valuable furbearing animals and show animals for increased rate of hair growth.

EXAMPLE 10 Related Compounds

Following the procedure of the preceding Examples, compositions aresimilarly prepared substituting an equimolar amount of a compound ofTable 1 for the bimatoprost disclosed in the preceding Examples. Similarresults are obtained.

While the preferred embodiment of the invention has been illustrated anddescribed, it will be appreciated that various changes can be madetherein without departing from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A method of increasing at least one attribute selected from the groupconsisting of thickness of hair, conversion of intermediate to terminalhair, number of hair, rate of hair growth of hair and density of haircomprising administering an effective amount of bimatoprost with asecond therapeutic agent selected from the group consisting ofestradiol, oxandrolone, minoxidil, procipia and agents which block theconversion of testosterone to dihydrotestosterone.
 2. The method ofclaim 1 wherein the second therapeutic agent is minoxidil.
 3. The methodof claim 2 wherein the bimatoprost and minoxidil are applied to oneselected from the group consisting of an eyelid margin, eyebrow, faceand scalp.
 4. The method of claim 1 wherein bimatoprost and the secondtherapeutic agent are administered together.
 5. The method of claim 4wherein the bimatoprost and second therapeutic agent are formulated in atopical composition.
 6. The method of claim 2 wherein the bimatoprostand second therapeutic agent are applied at least once a day.
 7. Themethod of claim I wherein the second therapeutic agent is an agent whichblocks the conversion of testosterone to dihydrotestosterone.
 8. Themethod of claim 1 wherein the bimatoprost is present in an amount of0.0000001% to about 50% by weight of the composition.
 9. The method ofclaim 8 wherein bimatoprost is present in an amount of 0.03% w/v. 10.The method of claim 5 wherein the bimatoprost and minoxidil areformulated as a cream.
 11. The method of claim 1 wherein applyingbimatoprost with a second therapeutic agent increases rate of hairgrowth and the conversion of intermediate to terminal hair.
 12. Themethod of claim 2 wherein the bimatoprost and minoxidil are applied tothe scalp.
 13. The method of claim 2 wherein the bimatoprost andminoxidil are applied to the eyelid margin.
 14. The method of claim 2wherein the bimatoprost and minoxodil are applied to the face.
 15. Themethod of claim 2 wherein the bimatoprost and minoxidil are appliedtogether in a dermatologically acceptable carrier.
 16. The method ofclaim 15 wherein the dermatologically acceptable carrier is selectedfrom the group consisting of aqueous solutions, oil solutions, creams,emulsions, ointments, linaments, shampoos, lotions, pastes, sprays andaerosols.
 17. The method of claim 15 wherein the dermatologicallyacceptable carrier is comprised of at least one selected from the groupconsisting of polysorbate, polyethylene glycol, hyaluronic acid,methylcellulose and polysaccharides.
 18. The method of claim 17 whereinpolysorbate is polysorbate
 80. 19. The method of claim 17 furthercomprising a preservative.
 20. The method of claim 19 wherein thepreservative is selected from the group consisting of benzalkonioumchloride, borate, chlorohexadine, chlorobutanol, parahydroxybenxoicacids and phemylmercuric acids.